Biomaterials research最新文献

Osteoarthritis (OA) is a common age-related degenerative disease characterized by changes in the local tissue environment as inflammation progresses. Inspired by the wind-dispersal mechanism of dandelion seeds, this study develops responsive biomimetic microsphere-drug conjugate for OA therapy and protection. The conjugate integrates dibenzaldehyde polyethylene glycol (DFPEG) with chitosan and polyethylene glycol diacrylate (PEGDA) through dynamic covalent bonds to form a dual-network hydrogel microsphere. Based on the progression of OA, the conjugate with the surface-anchored cyclic peptide cortistatin-14 (CST-14) achieves targeted drug therapy and a self-regulating hydrogel network. In cases of progressing inflammation (pH < 5), CST-14 dissociates from the microsphere surface (viz. the drug release rate increased) and inhibits TNF-α signaling to suppress OA. Concurrently, the monomer DFPEG responsively detaches from the hydrogel network and scavenges reactive oxygen species (ROS) to protect the cartilage tissue. The ROS scavenging of DFPEG is comparable to that of coenzyme Q10 and vitamin C. The degraded PEGDA microspheres provide tissue lubrication through reused conjugates. The rat OA model successfully achieved a synergistic therapeutic effect greater than the additive effect (1 + 1 > 2). This strategy offers an approach for anchoring amine-containing drugs and has marked potential for OA treatment and protection.

Smooth muscles play a vital role in peristalsis, tissue constriction, and relaxation but lack adequate self-repair capability for addressing extensive muscle defects. Engineering scaffolds have been broadly proposed to repair the muscle tissue. However, efforts to date have shown that those engineered scaffolds focus on cell alignment in 2-dimension (2D) and fail to direct muscle cells to align in 3D area, which is irresolvable to remodel the muscle architecture and restore the muscle functions like contraction and relaxation. Herein, we introduced an iron oxide (Fe₃O₄) filament-embedded gelatin (Gel)-silk fibroin composite hydrogel in which the oriented Fe₃O₄ self-assembled and functioned as micro/nanoscale geometric cues to induce cell alignment growth. The hydrogel scaffold can be designed to fabricate aligned or anisotropic muscle by combining embedded 3D bioprinting with magnetic induction to accommodate special architectures of muscular tissues in the body. Particularly, the bioprinted muscle-like matrices effectively promote the self-organization of smooth muscle cells (SMCs) and the directional differentiation of bone marrow mesenchymal stem cells (BMSCs) into SMCs. This biomimetic muscle accelerated tissue regeneration, enhancing intercellular connectivity within the muscular tissue, and the deposition of fibronectin and collagen I. This work provides a novel approach for constructing engineered biomimetic muscles, holding significant promise for clinical treatment of muscle-related diseases in the future.

The pathogenesis of temporomandibular joint osteoarthritis (TMJOA) is closely associated with mechanical friction, which leads to the up-regulation of inflammatory mediators and the degradation of articular cartilage. Injectable drug-loaded microparticles have attracted widespread interest in intra-articular treatment of TMJOA by providing lubrication and facilitating localized drug delivery. Herein, a hyaluronic acid-based microparticle is developed with excellent lubrication properties, drug loading capacity, antioxidant activity, and anti-inflammatory effect for the treatment of TMJOA. The microparticles are facilely prepared by the self-assembly of 3-aminophenylboronic acid-modified hyaluronic acid (HP) through hydrophobic interaction in an aqueous solution, which can further encapsulate diol-containing drugs through dynamic boronate ester bonds. The resulting microparticles demonstrate excellent injectability, lubrication properties, radical scavenging efficiency, and antibacterial activity. Additionally, the drug-loaded microparticles exhibit a favorable cytoprotective effect on chondrocyte cells in vitro under an oxidative stress microenvironment. In vivo experiments validate that intra-articular injection of drug-loaded microparticles effectively alleviates osteoporosis-like damage, suppresses inflammatory response, and facilitates matrix regeneration in the treatment of TMJOA. The HP microparticles demonstrate excellent injectability and encapsulation capacity for diol-containing drugs, highlighting its potential as a versatile drug delivery vehicle in the intra-articular treatment of TMJOA.

Along with a paradigm shift in looking at soft tissue fillers from space-filling to bioactive materials, decellularized extracellular matrix (DEM) fillers have gained more attention considering their superior bioactivity. However, the complex mechanisms that govern the interaction between host tissues and DEMs have been partially understood. This review first covers the mechanisms that determine immunogenicity, angiogenesis and vasculogenesis, and recellularization and remodeling after DEM implantation into host tissue, with a particular focus on related findings from filler materials. Accordingly, the review delves into the dual role of macrophages and their M1/M2 polarization paradigm to form both constructive and destructive immune responses to DEM implants. Moreover, the contribution of macrophages in angiogenesis has been elucidated, which includes but is not limited to the secretion of angiogenic growth factors and extracellular matrix (ECM) remodeling. The findings challenge the traditional view of immune cells as solely destructive entities in biomaterials and indicate their multifaceted roles in tissue regeneration. Furthermore, the review discusses how the compositional factors of DEMs, such as the presence of growth factors and matrikines, can influence angiogenesis, cell fate, and differentiation during the recellularization process. It is also shown that the biomechanical properties of DEMs, including tissue stiffness, modulate cell responses through mechanotransduction pathways, and the structural properties of DEMs, such as scaffold porosity, impact cell-cell and cell-ECM interactions. Finally, we pointed out the current clinical applications, the bottlenecks in the clinical translation of DEM biomaterials into soft tissue fillers, as well as the naïve research areas of the field.

Skull defect repair is a complex and critical medical challenge, and there is an urgent need to develop multifunctional tissue engineering scaffolds for skull regeneration. The success of bone tissue engineering depends on the construction of scaffolds that can regulate the immune microenvironment of bone regeneration and mimic the liquid crystal and viscoelastic properties of natural bone extracellular matrix. Hence, a smart hydrogel (PEGDA5/AM15/CLC-BMP-4@MBG) with good biocompatibility and the ability to modulate the wound immune microenvironment has been developed for the repair of skull defects. The hydrogel consists of chitin liquid crystal hydrogel (PEGDA5/AM15/CLC) and mesoporous bioactive glasses (MBGs) loaded with bone morphogenetic protein-4 (BMP-4). The liquid crystal hydrogel not only offers the necessary biological support and mechanical properties but also maintains the stability of the liquid crystal state, facilitating adhesion and regeneration of surrounding bone tissue. In addition, BMP-4@MBG intelligently regulates the release rate of BMP-4 in response to changes in wound microenvironment, thus effectively promoting the transformation of macrophages from M1 to M2 macrophages. At the same time, Ca²⁺ and Si⁴⁺ released by MBG degradation and BMP-4 synergically promote bone repair process. The PEGDA5/AM15/CLC-BMP-4@MBG hydrogel shows excellent immunomodulatory and osteogenic properties of bone microenvironment and is a promising scaffold material for bone tissue engineering.

The rapid identification of bacterial Gram types and their viability, as well as efficient bacterial elimination are crucial for managing bacterial infections yet present important challenges. In this research, we utilized long-chain-tailed BODIPY derivatives to address these hurdles. Our data indicated that these derivatives can distinguish bacteria types and their viability in aqueous solutions through a concise turn-on fluorescent response. Among them, B-8 stained both live and dead bacteria, and B-14 offered a wash-free staining. B-18 demonstrated the highest affinity to selectively fluorescent label viable gram-positive bacteria with a 53.2-fold fluorescent enhancement. Confocal imaging confirmed that B-18 can serve as an effective membrane-specific probe for facilitating the typing between gram-negative and gram-positive bacteria in a wash-free manner. Additionally, B-18 displayed selective photodynamic inactivation at 1 μM toward gram-positive bacteria. In vivo studies variformed the ideal photodynamic therapeutic efficacy of B-18 against methicillin-resistant Staphylococcus aureus in mice wound infections.

Repairing and regenerating articular cartilage defects (ACDs) have long been challenging for physicians and scientists. The rise of injectable materials provides a novel strategy for minimally invasive surgery to repair ACDs. In this study, we successfully developed injectable materials based on collagen type II, achieving hyaline cartilage repair and regeneration of ACDs. Analysis was conducted on the regenerated cartilage after materials injection. The histology staining demonstrated complete healing of the ACDs with the attainment of a hyaline cartilage phenotype. The biochemical and biomechanical properties are similar to the adjacent native cartilage without noticeable adverse effects on the subchondral bone. Further transcriptome analysis found that compared with the Native cartilage adjacent to the defect area, the Regenerated cartilage in the defect area repaired with type II collagen-based injection materials showed changes in cartilage-related pathways, as well as down-regulation of T cell receptor signaling pathways and interleukin-17 signaling pathways, which changed the immune microenvironment of the ACD area. Overall, these findings offer a promising injectable approach to treating ACDs, providing a potential solution to the challenges associated with achieving hyaline cartilage in situ repair and regeneration while minimizing damage to the surrounding cartilage.

Processing of bone allografts with strong acids and γ-sterilization results in decreased biomechanical properties and reduction in osteogenecity and osteoconductivity. High hydrostatic pressure (HHP) treatment could be a gentle alternative to processing techniques usually applied. HHP is known to induce devitalization of cancellous bone while preserving biomechanical stability and molecules that induce cell differentiation. Here, a specific HHP protocol for devitalization of cancellous bone was applied to rabbit femoral bone. Allogeneic bone cylinders were subsequently implanted into a defect in the lateral condyles of rabbit femora and were compared to autologous bone grafts. Analysis of bone integration 4 and 12 weeks postoperatively revealed no differences between autografts and HHP-treated allografts regarding the expression of genes characteristic for bone remodeling, showing expression niveous comparable to original bone cylinder. Furthermore, biomechanical properties were evaluated 12 weeks postoperatively. Autografts and HHP-treated allografts both showed a yield strength ranging between 2 and 2.5 MPa and an average bone mass density of 250 mg/cm². Furthermore, histological analysis of the region of interest revealed a rate of 5 to 10% BPM-2 and approximately 40% osteocalcin-positive staining, with no marked differences between allografts and autografts demonstrating comparable matrix deposition in the graft region. A suitable graft integrity was pointed out by μCT imaging in both groups, supporting the biomechanical data. In summary, the integrity of HHP-treated cancellous bone allografts showed similar results to untreated autografts. Hence, HHP treatment may represent a gentle and effective alternative to existing processing techniques for bone allografts.

Background: As one of the most aggressive and lethal cancers, pancreatic cancer is highly associated with cancer-associated fibroblasts (CAFs) that influence the development and progression of cancer. Targeted reprogramming of CAFs may be a promising strategy for pancreatic cancer. This study aims to construct engineered extracellular vesicles (EVs) with surface modification of integrin α5 (ITGA5)-targeting peptide and high internal expression of miR-148a-3p by endogenous modification for targeted reprogramming of pancreatic CAFs. Methods: Bone marrow mesenchymal stem cells (BMSCs) and pancreatic CAFs were cocultured to examine the effect of BMSC-derived EVs on the expression levels of CAF markers. miR-148a-3p was identified as a functional molecule. The mechanism of miR-148a-3p was elucidated using the dual-luciferase reporter assay. BMSCs were infected with TERT-encoding and miR-148a-3p-encoding lentiviruses. Subsequently, BMSCs were modified with ITGA5-specific targeting peptide. The supernatant was ultracentrifuged to obtain the engineered EVs (ITGA5-EVs^-148a), which were used to reprogram CAFs. Results: BMSCs modulated CAF marker expressions through EVs. miR-148a-3p was up-regulated in BMSCs. The expression of miR-148a-3p in pancreatic CAFs was down-regulated when compared with that in normal fibroblasts (NFs). Mechanistically, ITGA5-EVs^-148a effectively suppressed the proliferation and migration of pancreatic CAFs by targeting ITGA5 through the TGF-β/SMAD pathway. ITGA5-EVs^-148a was associated with enhanced cellular uptake and exhibited enhanced in vitro and in vivo targeting ability. Moreover, ITGA5-EVs^-148a exerted strong reconfiguration effects in inactivating CAFs and reversing tumor-promoting effects in 3D heterospheroid and xenograft pancreatic cancer models. Conclusions: This targeted CAF reprogramming strategy with genetically engineered ITGA5-EVs^-148a holds great promise as a precision therapeutics in clinical settings.

Periodontitis is a chronic inflammatory disease characterized by plaque accumulation, resulting in immune microenvironment disorders and resorption of alveolar bone. To promote bone healing under inflammatory environments, a functional biomaterial based on disease pathophysiology is designed. A novel fatty acid C10-modified polypeptide, C₁₀-KR8, is discovered to have excellent abilities in modulating macrophage repolarization and promoting bone regeneration in periodontitis. To build a multifunctional material localized drug delivery system, C₁₀-KR8@ZIF-8 (C₁₀-KR8-loaded zeolitic imidazolate framework-8) nanoparticles are constructed to sustainedly release the C₁₀-KR8 peptide and Zn elements. By synergistic effects of providing a dynamic immuno-modulatory environment and promoting osteogenesis under pathological conditions, the obtained pH-responsive nanoparticles display excellent bone regeneration capability. Furthermore, coimmunoprecipitation/liquid chromatography-tandem mass spectrometry analysis and proteomics analysis revealed that the C₁₀-KR8 peptide directly interacts with the high-temperature requirement protein A1 (Htra1), and C₁₀-KR8@ZIF-8 nanoparticles promote the osteogenic differentiation of bone mesenchymal stem cells by activating the focal adhesion kinase (FAK)/phosphatidylinositide 3-kinase (PI3K)/AKT pathway and enhancing the nuclear localization of Yes-associated protein (YAP). Taken together, this study demonstrates C₁₀-KR8 peptide regulate osteoimmunology and bone regeneration by Htra1/FAK/YAP pathway and that ZIF-8-based peptide loading platform is a promising strategy for periodontitis.